Morphology of Myelin

Myelin is a spiral membranous structure that is tightly wrapped around axons. It has a very high lipid content and is soluble in fat solvents. Hence, when ordinary paraffin sections of the brain are prepared for light microscopic examination, most of the myelin dissolves away. After staining, the sites where myelin was present appear as round spaces that are empty except that each has a little round dot in the center, which represents a cross section of the axon. By means of fixatives that make myelin insoluble, it is possible to demonstrate it in paraffin sections. Osmic acid fixes myelin so that it does not dissolve in paraffin sections. Osmic acid itself stains myelin black. When examined under very low power, the white matter appears black (Fig. 1.1). If the white matter is examined under high power the myelin will be seen to be arranged in small rings around each nerve fiber. There are several myelin stains that can be used once the tissue has been fixed by some other means. Commonly used stains include hematoxylin, Luxol fast blue, and Oil-Red-O.

Sclerosis Lines XrayMyelin Sheath MicroscopeWater Between Myelin Layers

The information derived from light microscopic investigations is limited and is inadequate when more detailed information about myelin structure is required. Analysis of the structure of myelin began in the 1930s, stimulated by polarization-microscope studies and X-ray diffraction work, which led to the suggestion that the myelin sheath was made up of layers or lamellae. The lamellar structure was confirmed by electron microscopic studies. In electron micrographs myelin is seen as a series of alternating dark and less dark lines separated by unstained zones. These lines are wrapped spirally around the axon (Fig. 1.2). The evidence available from studies using polarized light, X-ray diffraction and electron microscopy led to the current view of myelin as a system of condensed plasma membranes with alternating protein-lipid-protein-lipid-protein lamellae as the repeating subunit.

Plasma membranes are composed predominantly of lipids and proteins, and also contain carbohydrate components. The lipid elements of the membranes are phospholipids, glycolipids, and cholesterol. A common property of these lipids is that they are am-phipathic. This means that the lipid molecules contain both hydrophobic and hydrophilic regions, corresponding to the nonpolar tails and the polar head groups, respectively. Hydrophobic substances are in soluble in water, but soluble in oil. Conversely, hy-drophilic substances are insoluble in oil, but soluble in water. In an aqueous environment, the amphipa-thic character of the lipids favors aggregation into micelles or a molecular bilayer.In a micelle (Fig. 1.3),the hydrophobic regions of the amphipathic molecules are shielded from water, while the hydrophilic polar groups are in direct contact with water. The stability of this structure lies in the fact that significant free energy is required to transfer a nonpolar molecule from a nonpolar medium to water. Likewise, a great deal of energy is required to transfer a polar moiety from water to a nonpolar medium. Thus, the micelle provides a minimal energy configuration and is accordingly thermo dynamically stable. The molecular bilayer, the basic structure of plasma cell membranes, also satisfies the thermodynamic requirements of amphipathic molecules in an aqueous environment. A bilayer exists as a sheet in which the hydrophobic regions of the lipids are protected from the water while the hydrophilic regions are immersed in water (Fig. 1.4). As the structure of the bilayer is an inherent part of the amphipathic character of the lipid molecules, the formation of lipid bilayers is essentially a self-assembly process.

In comparison with other molecular bilayers, the myelin bilayer is unique in having a very high lipid

1.2 Morphology of Myelin 3

Fig. 1.5. Membrane split open to demonstrate the layers.The lipid bilayer is interrupted by proteins embedded in this layer.Glycoprotein chains rise from the surface of the membrane

1.2 Morphology of Myelin 3

Fig. 1.5. Membrane split open to demonstrate the layers.The lipid bilayer is interrupted by proteins embedded in this layer.Glycoprotein chains rise from the surface of the membrane

Rod Like Glycoprotein

content and containing chiefly saturated fatty acids with an extraordinarily long chain length. This fatty acid composition leads to a closely packed,highly stable membrane structure. The presence of unsaturated fatty acids in a bimolecular leaflet leads to a more loosely packed, less stable structure, as unsaturated fatty acid chains have a kinked, hook-like configuration. Lipids containing such unsaturated fatty acids cannot approach neighboring molecules as closely as saturated lipids can, since the latter are rod-like structures. There will be much less total interaction between the tails of an unsaturated lipid and a neighboring molecule than between the tails of two saturated lipids, and the resulting binding forces will be much smaller. Lipids containing long-chain fatty acids are more tightly held in a membrane structure than those containing shorter chain fatty acids, since with increasing length of the hydrocarbon chain the binding interactions between the lipid molecules become stronger. It has also been suggested that very-long-chain fatty acids can form complexes by inter-digitation of the hydrocarbon tail on one side with the hydrocarbon tail of a lipid on the opposite side of the bimolecular leaflet. Such complexes would contribute to the stability of the myelin membrane. If this lipid composition is changed, as is the case in a number of demyelinating disorders, it is clear that the stability of the myelin membrane may be diminished.

The bimolecular lipid structure allows for interaction of amphipathic proteins with the membrane. These proteins form an integral part of the membrane, with hydrophilic regions protruding from the inner and outer faces of the membrane and connected by a hydrophobic region traversing the hydrophobic core of the bilayer. In addition, there are peripheral proteins, which do not interact directly with the lipids in the bilayer,but are bound to the hydrophilic regions of specific integral proteins. Thus, the cell membrane is a bimolecular lipid leaflet coated with proteins on both sides (Fig. 1.5). There is inside-outside asymmetry of the lipids. In addition, integral and peripheral proteins are asymmetrically distributed across the membrane bilayer and the protein composition on the inside is different from that on the outside of the bilayer.

On electron microscopic examination, a plasma membrane is shown as a three-layered structure and consists of two dark lines separated by a lighter interval. It is also revealed that the plasma membrane is not symmetrical in form: the dark line adjacent to the cytoplasm is denser than the leaflet on the outside.

From both X-ray diffraction and electron microscope data it can be seen that the smallest radial subunit that can be called myelin is a five-layered structure of protein-lipid-protein-lipid-protein (Fig. 1.6). The repeat distance is 160-180 A. The dark lines seen in electron microscopic studies represent the protein layers and the unstained zones,the lipids. The uneven staining of the protein layers results from the way the myelin sheath is generated from the plasma membrane. The less dark lines (so-called intraperiod lines) represent the closely apposed outer protein coats of the original cell membrane. The dark lines (so-called major dense lines) are the fused inner protein coats of the cell membrane. High-magnification electron micrographs show that the intraperiod line is double in nature (Fig. 1.6).

The myelin sheath is not continuous along the entire length of axons, but axons are covered by segments of myelin,which are separated by small regions of uncovered axon, the nodes of Ranvier. The myelin lamellae terminate as they approach the node. The region where the lamellae terminate is known as the paranode. Electron micrographs of longitudinal sections of paranodal regions show that the major dense lines open up and loop back upon themselves,enclos-ing cytoplasm within the loop (Fig. 1.7). In that part of the paranode most distant from the node, the innermost lamellae of the myelin terminate first, and succeeding turns of the spiral of lamellae then overlap and project beyond the ones lying beneath. Thus, the outermost lamella overlaps all the others and terminates nearest the node, so that the myelin sheath

Lamellae Myelin Sheath

Fig. 1.6. The electron microscopic picture of a myelin sheath (upper left) reveals the five-layered structure of myelin with major dense lines and intraperiod lines. A higher magnification of two myelin lamellae (lower left) shows the periodicity of myelin even more clearly.On the right,a schematic representation of an electron microscopic picture of a myelin sheath surrounding an axon (A) demonstrates major dense lines (md) and intraperiod lines (ip)

Fig. 1.6. The electron microscopic picture of a myelin sheath (upper left) reveals the five-layered structure of myelin with major dense lines and intraperiod lines. A higher magnification of two myelin lamellae (lower left) shows the periodicity of myelin even more clearly.On the right,a schematic representation of an electron microscopic picture of a myelin sheath surrounding an axon (A) demonstrates major dense lines (md) and intraperiod lines (ip)

Electron Node Ranvier
Fig. 1.7. Node of Ranvier,where the nerve fiber between two myelinated segments is bare.The outer myelin layers envelope the inner layer and cover these at the nodal junctions

gradually becomes thinner with increasing proximity to the node.

Schmidt-Lantermann clefts such as are described in the PNS are rare in the CNS. These are funnel-shaped clefts within myelin sheaths. They contain cytoplasm and extend from the soma of the myelin-forming cell to the inner end of the myelin sheath. In a transverse section of a myelin sheath they appear as islands of cytoplasm between openings of the major dense lines.

There is considerable variation in the number of myelin lamellae in the sheaths surrounding different axons. Generally, the larger the diameter of the axon the thicker its myelin sheath. In addition to this direct relationship between axon size and myelin thickness, the lengths of internodal segments also vary with the size of the axon: the larger the nerve fiber, the greater the internodal length.

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  • Leona MacDonald
    What is myelin made up?
    8 years ago

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